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The battle between host and microbe

Auteur: Kevin Kosterman | Publicatiedatum:

Jos van Strijp is investigating why MRSA is so clever at avoiding the immune system. ‘People have never realised that a bacterium might be able to fight back.’

Jos van Strijp feels the Utrecht Science Park is the perfect place for him. The professor of medical microbiology works for the UMC together with the bèta-faculty, the veterinary faculty and the Hubrecht Laboratory to map precisely how bacteria are able to avoid the immune system. ‘S. aureus makes numerous very clever molecules that somehow are able to fool, block or destroy the immune system’, he says.

Van Strijp demonstrated some of these proteins as far back as 15 years ago. Among other things he used CHIPS to show that S. aureus destroys the immune system locally in order to survive.

Van Strijp identifies his field as bacterial medicine: understanding how bacteria and their hosts either communicate or fight one another. ‘Some of my assistants look into the molecular side, others into the cellular and yet others into the veterinary aspect. But the battle between host and microbe is key for them all.’

Will you witness another vaccine?

‘No, because I’m putting my money on the antibodies. Developments in this field are going so rapidly that that is where I expect the most to happen. And by the way, I more envisage a set of five antibodies than a single antibody. The same applies with regard to vaccines. A single component in a vaccine does not work. MRSA is by no means a simple organism. We’ve had all of those. You isolate them, nurture them, heat them up, inject them and you’ve got protection. We tried that some 40 years ago with staphylococci and every year since then, but it doesn’t work. People have injected billions of euros in the staphylococcus and have had no result whatsoever.’

What is so different now?

‘Most groups were looking for a target on the surface of the bacterium or a toxin against the bacterium. We chose immune evasion as our target and see all bacterium toxins as immune evasion proteins. Over the past few years we have demonstrated that toxins of S. aureus destroy white blood cells. They are highly specific given that they are not toxic for the rest of the body.’

Has that specificity also delayed your research?

‘Yes. Everyone across the world is using a useless model: the mouse. That is certainly one of the reasons why there is still no vaccine. Some 20 years ago people concluded that the mouse is not a good model, and yet the American drug authority FDA still stuck with it. A growing number of people, for instance in cancer research, are now saying that it is not a good model, just like the CEOs of large companies or the editors of Nature. It amazes me how difficult it is to break through that pattern. You still get the answer: you have to demonstrate it in the mouse.’

What’s wrong with the model?

‘Half the molecules we have discovered in S. aureus over the past few years are human-specific. They do not fit the receptors in the mouse or rabbit. Another aspect is also seen in our research on cows. It so happens that cows are also bothered by S. aureus in the form of mastitis, or inflammation of the udder. To illustrate how we work: you inject 500 million staphylococci into a mouse to infect it. You need one hundred bacteria to infect a cow. That in itself shows the difference. The cow staphylococcus differs from the one that infects humans, but the cow is a good infection model.

‘I’ll put my money on the antibodies’

The fact of the matter is that you see an enormous inflammatory reaction with those 500 million bacteria; while that is not the case if it was you being infected. We suspect that in humans – unfortunately we cannot put it to the test – infection starts with a maximum of one thousand bacteria. That’s why I find a cow a good model. It works differently at molecular level, but you can learn a great deal from the working mechanism. It’s a pity that cows are so expensive, too slow and they don’t die fast enough.’

Can you use a different organism?

‘We have been unsuccessful in our search all around the world and so we are making one ourselves. We are attempting to modify mice, but that process is too slow. We are currently working on zebrafish that we modify with CRISPR-Cas. Simultaneously we are attempting to modify the bacteria so that they do work in mice. That will result in the same effect as in cows. You can use such a model for this principle. That would enable you to reduce the dose in mice and thus arrive at a more realistic model. That could be useful. If you look at the S. aureus toxins then you see that all but one are human-specific. Alpha toxin is the only toxin that also works in mice. And what’s happening now? All pharmaceutical companies are starting to focus on this.’

But isn’t that the wrong reason, just because it’s easy to test?

‘That’s a conclusion you draw straight away, but the pharmaceutical company CEOs don’t. They read the literature and come across alpha toxin and see that you can test it. And subsequently they pump billions of euros in relevant research. But they are gradually seeing the light. When I speak with pharmacists I inevitably hear: 'Great, those fifty proteins, but which of those fifty should we make our target?' S. aureus uses fifty to shut down the immune system and the pharmaceutical industry wants to do it with a single one. That’s not going to work, so I always say: try it now with at least three! They don’t like to hear me say that.’

Does classical immunology still stand?

‘The field has always regarded a bacterium as a globule that is devoured by a white blood cell, but never considered that this globule might be able to fight back. The latter is clearly the case.’

How does a bacterium fight back?

‘It can fight back with toxins. These proteins keep neutrophils at bay. You can divide the proteins produced by a bacterium into three groups. Proteins on the inside of the cell, proteins on the surface, and the proteins secreted by the bacterium. We know 95 % of the proteins in the cell. They are easy to find because they are so large. We also know some 90 % of the cell surface genes. We are looking at the secreted proteins. We know what the function is of approximately 20 % of these. If you consider that your microbiome contains some 3,000 sorts of bacteria that secrete about 10 % of their protein, then you are looking at about a million secreted proteins of which you have no idea what they do. So that’s the challenge.’

 But there are other defence mechanisms as well.

‘Making a thick envelope, like pneumo-cocci do, is another form of immune evasion. However, at the moment of infection you have to peel off the envelope momentarily, for example at the point of attachment, and that’s when you become vulnerable. Another option is to enter a cell. Tuberculosis has mastered this perfectly. It lives in a macrophage all its life. Until 15 years ago we were unable to do anything about this. However, it was discovered that also the inside of a cell has an immune system, for example by using the NOD-like receptors. The smartest bacteria also combine these three strategies. Only then might a bacterium survive a couple of days inside a host.’

And yet the concept of evasion is not new.

‘No, in the 1950s and 1960s minute worms were shown to be able to nestle in the skin without the skin becoming red. These worms must produce something that fools the immune system. In actual fact, immune evasion therefore originated in parasitology. We took this immune evasion up some 15 years ago and developed it further for bacteriology. CHIPS gave rise worldwide to a reaction of ‘Oh, can bacteria do that as well?’ Of course they can; they have more genes than viruses and they can do it too. If a pathogen is to survive inside a host it must use immune evasion. If a bacterium fails to do that, then it can never survive as a pathogen: just give up and go and live in the ground.’

Is there sufficient funding for antibiotics resistance studies? MRSA has existed since the 1960s...

‘Some 20 years ago we knew about bacteria, we had antibiotics, thus there was consensus that you need no longer do research in this area. At least not so in-depth as we are doing with a group of forty researchers. However, the world now realises that we do need new drugs. It therefore takes many years before politics become convinced of this. Six months ago Dutch health minister Schippers visited our department, together with King Willem-Alexander. It was then decided to place antibiotic resistance at the top of the agenda during the Dutch presidency of the EU. However, two issues have since intervened: the terrorist attacks and refugees.’ He smiles: ‘Which are now receiving slightly more attention.’

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